The transforming growth factor-beta (TGF-beta) superfamily contains a variety of growth factors that share common sequence elements and structural motifs. These proteins are known to exert biological effects on a large variety of cell types in both vertebrates and invertebrates. Members of the superfamily perform important functions during embryonic development in pattern formation and tissue specification and can influence a variety of differentiation processes, including adipogenesis, myogenesis, chondrogenesis, cardiogenesis, hematopoiesis, neurogenesis, and epithelial cell differentiation. The superfamily includes proteins that are variously described as Growth and Differentiation Factors (GDFs), Bone Morphogenetic Proteins (BMPs), activins and inhibins.
By manipulating the activity of a member of the TGF-beta superfamily, it is often possible to cause significant physiological changes in an organism. For example, GDF8 (myostatin) is a well-known regulator of skeletal muscle mass and strength. The Piedmontese and Belgian Blue cattle breeds carry a loss-of-function mutation in the myostatin gene that causes a marked increase in muscle mass. Grobet et al., Nat Genet. 1997, 17(1):71-4. Furthermore, in humans, inactive alleles of GDF8 are associated with increased muscle mass and, reportedly, exceptional strength. Schuelke et al., N Engl J Med 2004, 350:2682-8. Other members of the superfamily, such as activin A, are also reported to regulate skeletal muscle. Modulators of GDF8 and activin are in clinical development for the treatment of muscle conditions. Antibodies directed to myostatin promote muscle formation in animal models, although results in human clinical trials have not demonstrated prominent increases in skeletal muscle mass or strength, raising a question as to whether other members of the TGF-beta superfamily may regulate muscle growth. Walker et al., Ann Neurol. 2008, 63:561-71. The activin receptor type IIB (ActRIIB, also known as ACVR2B), is a high affinity receptor for myostatin, activin A and other members of the TGF-beta superfamily, including GDF11 and other activins. Lee et al. Proc Natl Acad Sci USA 2005, 102:18117-22; Mathews et al. Science 1992 255:1702-5; WO 00/43781; WO 2006/012627. An ActRIIB-Fc fusion protein acts as a high affinity antagonist to each of these ligands and promotes substantial muscle growth in animal models as well as humans. Lee et al. Proc Natl Acad Sci USA 2005, 102:18117-22; WO 2004/039948; WO 2006/012627; WO 2008/097541. ActRIIB-Fc is also known to promote bone formation and, in some cases, affect other tissues. WO 95/10611; Hamrick et al. Calcif Tissue Int 2002, 71:63-68; WO 2006/012627; WO 2008/097541. Similarly, it has been proposed that antibodies that bind to ActRIIB and disrupt ligand binding and/or signaling (e.g., neutralizing antibodies) can be used to promote muscle or bone formation and treat a variety of disorders. U.S. Pat. No. 6,656,475; WO 2006/012627; WO 2008/097541.
Thus, it is an object of this disclosure to provide antibodies that bind to ActRIIB and uses for same.